Anti-parasitic heterocycle compounds, agents, formulations, and methods of use thereof

ABSTRACT

Compounds of formula (I)wherein the substituents are as defined herein, are antiparasitic agents.

The present application is a divisional of U.S. Ser. No. 09/567,330,filed May 9, 2000, now abandoned which is a continuation of U.S. Ser.No. 09/452,423, filed Dec. 1, 1999, and now U.S. Pat. No. 6,110,958,which is a continuation of U.S. Ser. No. 09/310,815, filed May 12, 1999,and now U.S. Pat. No. 6,083,965. The present application also claimspriority under 35 USC section 119 of Great Britain provisionalspecification 9810354.2, itself filed May 14, 1998. The complete text ofthese prior applications is hereby incorporated by reference, as iffully set forth.

This invention relates to nitrogen-containing heterocyclic substanceshaving parasiticidal properties, in particular toN-aryl/heteroaryl-substituted heterocycles.

International Patent Application publication number WO98/24767 andEuropean Patent Application publication number EP 0 846 686 A1 disclosecertain 1-N-arylpyrazole substances with a 4-cyclopropyl moiety and a4-heterocyclyl moiety respectively, as having antiparasitic properties.

According to the present invention, there is provided a compound offormula (I),

wherein A is N or CR⁵,

B is Nor CR⁶,

wherein R⁵ and R⁶ are each independently selected from H, C₁₋₄ alkyloptionally substituted by one or more halo, CN and halo,

or when A and B are CR⁵ and CR⁶, respectively, they can be takentogether to form a fused benzo- or pyridino-ring,

which fused ring is optionally substituted by one or two halosubstituents and, when the pyridino-fused ring is present, optionallybears an oxide substituent on the nitrogen of said pyridino-ring,

R¹ is a 5-membered heteroaryl group selected from furan-2-yl,furan-3-yl, thien-2-yl, thien-3-yl and isoxazol-5-yl, each of which isoptionally substituted by one or two substituents independently selectedfrom halo, C₁₋₄ alkyl optionally substituted by one or more halo, and(C₁₋₄ alkyl optionally substituted by one or more halo)S(O)_(n), or R¹is a group of formula (II)

wherein R⁷ is H, C₁₋₄ alkyl optionally substituted by one or more halo,or C₁₋₄ alkoxy optionally substituted by one or more halo,

R⁸ and R⁹ are either each independently selected from H, chloro, fluoro,bromo and C₁₋₄ alkyl optionally substituted by one or more halo, or,when taken together with the carbon atom to which they are attached,form a C₃₋₆ cycloalkyl group,

R¹⁰ and R¹¹ are either each independently selected from H, chloro,fluoro, bromo and C₁₋₄ alkyl optionally substituted by one or more halo,or, when R⁸ and R⁹ taken together do not form part of a cycloalkylgroup, R¹⁰ and R¹¹ together with the carbon atom to which they areattached, form a C₅₋₇ cycloalkyl group,

E is N or CR², wherein

R² is H, NH₂, halo, NHCH₂(phenyl optionally substituted by C₁₋₄ alkoxy),CO₂(C₁₋₄ alkyl optionally substituted by one or more halo) orS(O)_(n)(C₁₋₄ alkyl optionally substituted by one or more halo),

X is N or CR¹², wherein

R¹² is halo.

R³ is halo,

R⁴ is C₁₋₄ alkyl optionally substituted by one or more halo, C₁₋₄ alkoxyoptionally substituted by one or more halo, S(O)_(n)(C₁₋₄ alkyloptionally substituted by one or more halo), halo or SF₅, and

n is 0, 1 or 2,

with the provisos that (i) when B is N, then A and/or E is also N, and(ii) when E is N then A and/or B is also N,

or a pharmaceutically-, agriculturally- or veterinarily-acceptable saltthereof, or solvate of any such compound or salt (hereinafter referredto as “the substances of the invention”).

Alkyl groups may be straight or branched where the number of carbonatoms allows. S(O)_(n)alkyl and alkoxy groups incorporate such alkylmoieties. Halo means fluoro, chloro, bromo or iodo.

Pharmaceutically-, agriculturally or veterinarily-acceptable salts arewell-known in the art and include, for example those mentioned by Bergeet al in J.Pharm.Sci., 66, 1-19 (1977). Suitable acid addition salts areformed from acids which form non-toxic salts and include thehydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate,phosphate, hydrogenphosphate, acetate, gluconate, lactate, salicylate,citrate, tartrate, ascorbate, succinate, maleate, fumarate, formate,benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate andp-toluenesulphonate salts.

Solvates (e.g. hydrates) are generally well-known in the art and can beprepared by standard methods.

Preferably the “ABNEC” ring moiety in the compound of formula (I) aboveis a pyrrol-1-yl, 1,2,3-triazol- 1 -yl, 1,2,4-triazol-1-yl,imidazol-1-yl or indol-1-yl moiety.

Preferably R⁵ is H, C₁₋₄ alkyl optionally substituted by one or morehalo, CN, or when B is CR⁶, together with the carbon atom to which it isattached and CR⁶, is a benzo- or pyridino-ring, which benzo- orpyridino-ring is optionally substituted by one or two halo groups, and,when the pyridino-ring is present, oxide on the nitrogen of saidpyridino-ring. More preferably R⁵ is H, CN, CH₃ or CF₃, or when B isCR⁶, together with the carbon atom to which it is attached and CR⁶, is abenzo- or pyridino-ring, which benzo- or pyridino-ring is optionallysubstituted by one or two fluoro groups, and, when the pyridino-ring ispresent, oxide on the nitrogen of said pyridino-ring. Most preferably R⁵is H, CH₃ or CN.

Preferably R⁶ is H, halo, C₁₋₄ alkyl optionally substituted by one ormore halo, or when A is CR⁵, together with the carbon atom to which itis attached and CR⁵, is a benzo- or pyridino-ring, which benzo- orpyridino-ring is optionally substituted by one or two halo groups, and,when the pyridino-ring is present, oxide on the nitrogen of saidpyridino-ring. More preferably R⁶ is H, halo, CH₃ or CF₃, or when A isCR⁵, together with the carbon atom to which it is attached and CR⁵, is abenzo- or pyridino-ring, which benzo- or pyridino-ring is optionallysubstituted by one or two fluoro groups, and, when the pyridino-ring ispresent, oxide on the nitrogen of said pyridino-ring. Most preferably,R⁶ is H, Cl, Br or CH₃.

Preferably R¹ is a furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl orisoxazol-5-yl group, each optionally substituted by one or twosubstituents independently selected from halo, C₁₋₄ alkyl optionallysubstituted by one or more halo, and (C₁₋₄ alkyl optionally substitutedby one or more halo)S(O)_(n), or R¹ is a group of formula (II)

wherein R⁷ is H or C₁₋₄ alkyl optionally substituted by one or morehalo, R⁸ and R⁹ are each independently selected from H, chloro, fluoroor bromo, and R¹⁰ and R¹¹ are both H. More preferably R¹ is furan-2-yl,furan-3-yl, thien-2-yl, thien-3-yl or isoxazol-5-yl group, eachoptionally substituted by one or two substituents independently selectedfrom fluoro, chloro, bromo, CF₃ and CH₃. or R¹ is a group of formula(II)

wherein R⁷ is H, CH₃ or CF₃, R⁸ and R⁹ are each independently selectedfrom H, chloro, fluoro or bromo, and R¹⁰ and R¹¹ are both H. Mostpreferably, R¹ is 3-bromisoxazol-5-yl, 2,2-dibromocyclopropyl,2,2-dichlorocyclopropyl or 1-trifluoromethylcyclopropyl.

Preferably R² is H, NH₂, halo or NHCH₂(phenyl optionally substituted byC₁₋₄ alkoxy). More preferably R² is H, NH₂, F, Cl or Br. Most preferablyR² is H or NH₂.

Preferably X is C-F, C-Cl or C-Br. More preferably X is C-Cl.

Preferably R³ is chloro.

Preferably R⁴ is methyl optionally substituted by one or more halo,methoxy optionally substituted by one or more halo, S(O)_(n)(methyloptionally substituted by one or more halo), halo or SF₅. Morepreferably R⁴ is CF₃, OCF₃, SCF₃ or SF₅.

The most preferred substances are those of the Examples below, and thesalts and solvates thereof.

The compounds of the formula (I) may possess one or more asymmetriccentres and so exist in two or more stereolsomeric forms. The presentinvention includes all the individual stereolsomers of the compounds offormula (I), salts, solvates and mixtures thereof.

Separation of diastereomers may be achieved by conventional techniques,e.g. by fractional crystallisation, chromatography such as H.P.L.C. of astereoisomeric mixture of a compound of formula (I) or a suitable saltor derivative thereof. An individual enantiomer of a compound of formula(I) may also be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereomeric salts formed by reaction of thecorresponding racemate with a suitably optically active acid or base.

The substances provided by the invention can be prepared by adaptationof methods disclosed in the art, specifically in the art relating toantiparasitic pyrazoles, such as in copending International PatentApplication publication number WO98/24767 and European PatentApplication publication number EP 0 846 686 A1, for instance by themethods specifically described in the Examples and Preparations sectionbelow, and suitable adaptation thereof. The synthetic chemist skilled inthe art will be aware of many transformations that can be used toconstruct the substances of the invention.

Exemplary synthetic methods are described below. In these methods thedefinitions for the various groups and substituents are as given abovefor compounds of formula (I), unless specified otherwise.

Method 1

Compounds of the formula (I) wherein R¹ is a group of formula (II)

can be made from the corresponding olefinic compound of formula (III) or(IV) below by a reaction which is formally regarded as a carbenetransfer or insertion reaction of a “R⁸R⁹C:” or “R¹⁰R¹¹C:” moiety asrequired.

Compounds of formulae (III) and (IV) can be made by conventionalmethods, for example by adaptation of the methods described for thecorresponding pyrazole-4-olefins in International Patent Applicationpublication number WO97/07102, which is herein incorporated byreference.

The carbene transfer/insertion reactions can be carried out by themethods described in various texts known in the art, such as “Carbenes,Nitrenes and Arynes” by T L Gilchrist and C W Rees, published by Nelson(1973), and “Advanced Organic Chemistry” by J March, 3rd edition,published by Wiley-Interscience (1985) (e.g. section 5-49 on pp768-774), both of which are herein incorporated by reference. The“R⁸R⁹C:” and “R¹⁰R¹¹C:” moieties may be generated from suitableprecursors known in the art.

Method 2

Compounds of formula (I) wherein R¹ is a 5-membered heteroaryl groupselected from furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl andisoxazol-5-yl, each of which is optionally substituted by one or twosubstituents independently selected from halo, CH₃, CF₃, andCF₃S(O)_(n), can be prepared by cross-coupling reactions, for examplepalladium-catalysed cross-coupling, of compounds of the formula (V):

with boronic acids of the formula ArB(OR)₂, where Ar is a 5-memberedheteroaryl group selected from furan-2-yl, furan-3-yl, thien-2-yl,thien-3-yl and isoxazol-5-yl, each of which is optionally substituted byone or two substituents independently selected from halo, CH₃, CF₃, andCF₃S(O)_(n). The reaction is carried out using a suitable palladium (0)species such as Pd(PPh₃)₄, in a suitable solvent or solvent system suchas N,N-dimethylformamide (DMF), ethanol/toluene/water, diglyme/water ordioxane/water, and using a suitable base such as NaHCO₃ or K₂CO₃. Thegeneral palladium-catalysed cross coupling chemistry is described by ARMartin and Y Yang in Acta chemica Scandinavica (1993), 47, 221-230.

Intermediates of formula (V) above can be made by reaction of compoundsof formula (VI)

with an iodinating or brominating species such as N-iodo- orN-bromosuccinimide in a suitable solvent such as acetonitrile.

Compounds of formula (VI) can be made by conventional methods and bysuitable adaptation of the methods described later in the Examples andPreparations section.

Boronic acids of the formula ArB(OH)₂, where Ar is as defined above, canbe made by conventional methods.

Method 3

Compounds of formula (I) where R¹ is 3-bromoisoxazol-5-yl can be made byreaction of compounds of the formula (VII):

with dibromoformaldoxime and a suitable base such as KHCO₃, in asuitable solvent or solvent system such as water/ethyl acetate.

Compounds of formula (VII) can be made by conventional methods and thosedescribed in the Examples and Preparations section and suitableadaptation thereof, and also as described for the correspondingpyrazole-4-alkynes in International Patent Application publication no.WO 97/07102, herein incorporated by reference.

Method 4

Compounds of the formula (I) where R¹ is 3-(iodo, bromo, orchloro)furan-2-yl can be made according to the reaction sequence shownbelow:

Compounds of formula (IX) can be made by oxidation of olefins of formula(E) or (IV) above where R⁷ is H, with a suitable oxidising regime suchas with osmium tetroxide/N-methylmorpholine oxide (NMMO)/sodiummetaperiodate. The reaction is carried out in a suitable solvent orsolvent system such as acetone/water.

Compounds of formula (X) can be made by reaction of aldehydes (LX) withthe lithium salt of propiolaldehyde diethyl acetal. Preferably thelithium salt of propiolaldehyde diethyl acetal is prepared in situ frompropoioaldehyde diethyl acetal and a suitable lithiating agent such asn-butyllithium. The reaction is preferably carried out in an ethersolvent such as tetrahydrofuran, and preferably under an inertatmosphere such as under dry nitrogen.

Compounds of formula (XI) where Y is chloro, bromo or iodo, can be madeby reaction of compounds of formula (X) with an acid such as aqueoushydro(chloric, bromic or iodic) acid. The reaction can be carried out ina suitable solvent such as dioxane. The cyclisation reaction is derivedfrom those described by Obrecht in Helv.Chim.Acta, vol.72 (1989) 447.

Method 5

Compounds of the formula (I) where R¹ is 5-(iodo, bromo orchloro)thien-2-yl can be made by reacting the corresponding compound offormula (I) where R¹ is thien-2-yl (preparable by Method 2) with aniodinating, brominating or chlorinating species respectively such as thecorresponding N-(iodo, bromo, or chloro)succinimide in a suitablesolvent such as acetonitrile.

Method 6

Compounds of the formula (I) where R¹ is5-trifluoromethylsulphenylthien-2-yl can be made by reacting thecorresponding compound of formula (I) where R¹ is thien-2-yl (preparableby Method 2) with trifluoromethylsulphenyl chloride and stannic chloridein a suitable solvent such as dichloromethane.

Method 7

Compounds of the formula (I) where R¹ is 3-(iodo, bromo, orchloro)4-(iodo, bromo, or chloro)-isoxazol-5-yl can be made by reactingthe corresponding compound of formula (I) where R¹ is 3-(iodo, bromo, orchloro)-isoxazol-5-yl (preparable by Methods above) with an iodinating,brominating or chlorinating species respectively such as thecorresponding N-(iodo, bromo, or chloro)succinimide in a suitablesolvent such as acetonitrile.

Method 8

Compounds of the formula (I) where R¹ is 2-trifluoromethylfuran-3-yl canbe made by reacting the corresponding compound of formula (I) where R¹is furan-3-yl (preparable by Method 2) with CF₃—Z where Z is a suitableleaving group such as Br, I, Cl, etc. with sodium dithionite anddisodium hydrogen phosphate in a suitable solvent such as DMF, underelevated pressure such as 1.37 bar to 3.1 bar (20 to 45 p.s.i.). Thistype of reaction is described in J.Chem.Soc., Perkin Transactions 2,(1990) 2293. CF₃-Z compounds can be made by conventional methods.

Method 9

Compounds of the formula (I) where R¹ is 2-(chloro or bromo)furan-3-ylcan be made by reacting the corresponding compound of formula (I) whereR¹ is furan-3-yl (preparable by Method 1) with chlorinating orbrominating agents such as N-(chloro or bromo)succinimide, asappropriate, in a suitable solvent such as acetonitrile.

Method 10

Compounds of the formula (I) where R¹ is2-trifluoromethylsulphenylfuran-3-yl can be made by reacting thecorresponding compound of formula (I) where R¹ is furan-3-yl (preparableby Method 2) with with trifluoromethylsulphenyl chloride and stannicchloride in a suitable solvent such as dichloromethane.

Method 11

Compounds of the formula (I) where E is CH can be made by reacting thecorresponding compound where E is CNH₂ with a suitable alkyl nitritesuch as t-butyl nitrite, in a suitable solvent such as tetrahydrofuran(THF).

Method 12

Compounds of the formula (I) where E is C-halo can be made by reactingreacting the corresponding compound where E is CNH₂ with a suitablealkyl nitrite such as t-butyl nitrite, and a halide source such asiodine, tribromomethane or CuCl₂, in a suitable solvent such astetrahydrofuran (THF).

Method 13

Compounds of the formula (I) where E is C-C₁₋₆, alkyl and R¹, Ar, R³,R⁴, R⁵, R⁶ and R⁷ are as defined before for compounds of formula (I),can be made by reacting the corresponding compound where E is C-iodowith a lithiating species such as n-butyllithium, to make thecorresponding 5-lithiated pyrazole, followed by reaction with analkylating species (C₁₋₆ alkyl—Z) where Z is a suitable leaving groupsuch as iodide or bromide.

The substances of the invention may be separated and purified byconventional methods.

It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of substances of the invention. This may be achieved byconventional techniques, for example as described in “Protective Groupsin Organic Synthesis” by T W Greene and P G M Wuts, John Wiley and SonsInc, 1991.

The substances of the invention are useful because they possessparasiticidal activity in humans, animals and plants. They areparticularly useful in the treatment of ectoparasites.

With regard to the use of the substances of the invention in humans,there is provided:

a) a pharmaceutical formulation comprising a substance of the inventionin admixture with a pharmaceutically acceptable adjuvant, diluent orcarrier which may be adapted for topical administration;

b) a substance of the invention, for use as a medicament;

c) the use of a substance of the invention in the manufacture of aparasiticidal medicament; and

d) a method of treating a parasitic infestation in a patient whichcomprises administering an effective amount of a substance of theinvention to the patient.

With regard to the use of the substances of the invention in non-humananimals, the substances may be administered alone or in a formulationappropriate to the specific use envisaged and to the particular speciesof host animal being treated and the parasite involved. The methods by

which the substances may be administered include oral administration bycapsule, bolus, tablet or drench, or as a pour-on or spot-onformulation, or alternatively, they can be administered by injection(e.g. subcutaneously, intramuscularly or intravenously), dip, spray,mousse, shampoo, powder, or as an implant.

Such formulations are prepared in a conventional manner in accordancewith standard veterinary practice. Thus capsules, boluses or tablets maybe prepared by mixing the active substance with a suitable finelydivided diluent or carrier additionally containing a disintegratingagent and/or binder such as starch, lactose, talc, magnesium stearateetc. Oral drenches are prepared by dissolving or suspending the activeingredient in a suitable medium. Injectable formulations may be preparedin the form of a sterile solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood. Acceptable liquid carriers include the vegetable oils such assesame oil and the like, glycerides such as triacetin and the like,esters such as benzyl benzoate, isopropyl myristate and fatty acidderivatives of propylene glycol and the like, as well as organicsolvents such as pyrrolidone, glycerol formal and the like. Theformulations are prepared by dissolving or suspending the activeingredient in the liquid carrier such that the final formulationcontains from, for instance, 0.01 to 10% by weight of the activeingredient.

These formulations will vary with regard to the weight of activesubstance contained therein depending on the species of host animal tobe treated, the severity and type of infection and the body weight ofthe host. For parenteral, topical (e.g. using pour-on or spot-on, dip,spray, mousse, shampoo or powder to deliver the compound) and oraladministration, typical dose ranges of the active ingredient are0.01-100 mg per kg of body weight of the animal. Preferably the range is0.1 to 10 g per kg.

As an alternative the substances of the invention may be administeredwith the animal feedstuff and for this purpose a concentrated feedadditive or premix may be prepared for mixing with the normal animalfeed.

The substances of the invention have utility in the control ofarthropod, plant nematode, helminth or protozoan pests. The substancesof the invention may, in particular, be used in the field of veterinarymedicine and livestock husbandry and in the maintenance of public healthagainst arthropods, helminths or protozoa which are parasitic internallyor externally upon vertebrates, particularly warm-blooded vertebrates,for example man and domestic animals, e.g. cattle, sheep, goats,equines, swine, poultry, dogs, cats and fish, for example Acarina,including ticks (e.g. Ixodes spp., Boophilus spp. e.g. Boophilusmicroplus, Amblyomma spp., Hyalomma spp., Rhipicephalus spp. e.g.Rhipicephalus appendiculatus, Haemaphysalis spp., Dermacentor spp.,Omithodorus spp. (e.g. Ornithodorus mouhata and mites (e.g. Damaliniaspp., Dermahyssus gallinae, Sarcoptes spp. e.g. Sarcoptes scabiei,Psoroptes spp., Chonioptes spp., Demodex spp., Eutrombicula spp.,)Diptera (e.g. Aedes spp., Anopheles spp., Musca spp., Hypoderrna spp.,Gastrophilus spp., Simulium spp.); Hemiptera (e.g. Triatoma spp.);Phthiraptera (e.g. Damalinia spp., Linoqnathus spp.) Siphonaptera (e.g.Ctenocephalides spp.); Dictyoptera (e.g. Periplaneta spp., Blatellaspp.); Hymenoptera (e.g. Monomorium pharaonis); for example againstinfections of the gastrointestinal tract caused by parasitic nematodeworms, for example members of the family Trichostrongylidae,Nippostronylus brasiliensis, Trichinella spiralis, Haemonchus contortus,Trichostronylus colubriformis, Nematodirus battus, Ostertagiacircumcincta, Trichostrongylus axei, Cooperia spp. and Hymenolepis nana,in the control and treatment of protozoal diseases caused by, forexample Eimeria spp. e.g. Eimeria tenella, Eimeria acervulina, Eimeriabrunetti, Eimeria maxima, Eimeria necatrix, Eimeria bovis, Eimeriazuerni and Eimeria ovinoidalis; Trypanosoma cruzi, Leishmania spp.,Plasmodium spp., Babesia spp., Trichomonadidae spp., Histomonas spp.,Giardia spp., Toxoplasma spp., Entamoeba histolytica and Theileria spp.;in the protection of stored products, for example cereals, includinggrain and flour, groundnuts, animal foodstuffs, timber and householdgoods, e.g. carpets and textiles, against attack by arthropods, moreespecially beetles, including weevils, moths and mites, for exampleEphestia spp. (flour moths), Anthrenus spp. (carpet beetles), Triboliumspp. (flour beetles), Sitophilus spp. (grain weevils) and Acarus spp.(mites), in the control of cockroaches, ants and termites and similararthropod pests in infested domestic and industrial premises and in thecontrol of mosquito larvae in waterways, wells, reservoirs or otherrunning or standing water; for the treatment of foundations, structureand soil in the prevention of the attack on buildings by termites, forexample, Reticulitermes spp., Heterotermes spp., Coptoterms spp.; inagriculture, against adults, larvae and eggs of Lepidoptera (butterfliesand moths), e.g. Heliothis spp. such as Heliothis virescens (tobaccobudworm), Heliothis armioera and Heliothis zea, Spodoptera spp. such asS. exempta, S. littoralis (Egyptian cotton worm), S. eridania (southernarmy worm), Mamestra configurata (bertha army worm); Earias spp. e.g. E.insulana (Egyptian bollworm), Pectinophora spp. e.g. Pectinophoragossypiella (pink bollworm), Ostrinia spp. such as O. nubilalis(European comborer), Trichoplusia ni (cabbage looper), Pieris spp.(cabbage worms), Laphyqma spp. (army worms), Agrotis and Amathes spp.(cutworms), Wiseana spp. (porina moth), Chilo spp. (rice stem borer),Tryporyza spp. and Diatraea spp. (sugar cane borers and rice borers),Sparganothis pilleriana (grape berry moth), Cydia pomonella (codlingmoth), Archips spp. (fruit tree tortrix moths), Plutella xylostella(diamond black moth); against adult and larvae of Coleoptera (beetles)e.g. Hypothenemus hampei (coffee berry borer), Hylesinus spp. (barkbeetles), Anthonomus grandis (cotton boll weevil), Acalymma spp.(cucumber beetles), Lema spp., Psylliodes spp., Leptinotarsadecemlineata (Colorado potato beetle), Diabrotica spp. (corn rootworms),Gonocephalum spp. (false wire worms), Agriotes spp. (wireworms),Dermolepida and Heteronychus spp. (white grubs), Phaedon cochleariae(mustard beetle), Lissorhoptrus oryzophilus (rice water weevil),Melioethes spp. (pollen beetles), Ceutorhynchus spp., Rhynchophorus andCosmopolites spp. (root weevils); against Hemiptera e.g. Psylla spp.,Bemisia spp., Trialeurodes spp., Aphis spp., Myzus spp., Megoura viciae,Phylloxera spp., Adelges spp., Phorodon humuli (hop damson aphid),Aeneolamia spp., Nephotettix spp. (rice leaf hoppers), Empoasca spp.,Nilaparvata spp., Perkinsiella spp., Pyrilla spp., Aonidiella spp. (redscales), Coccus spp., Pseucoccus spp., Helopeltis spp. (mosquito bugs),Lygus spp., Dysdercus spp., Oxycarenus spp., Nezara spp.; Nymenopterae.g. Athalia spp. and Cephus spp. (saw flies), Atta spp. (leaf cuttingants); Diptera e.g. Hylemyia spp. (root flies), Atherigona spp. andChlorops spp. (shoot flies), Phytomyza spp. (leaf miners), Ceratitisspp. (fruit flies); Thysanoptera such as Thrips tabaci: Orthoptera suchas Locusta and Schistocerca spp. (locusts) and crickets e.g. Gryllusspp. and Acheta spp.; Collembola e.g. Sminthurus spp. and Onychiurusspp. (springtails), Isoptera e.g. Odontotermes spp. (termites),Dermaptera e.g. Forficula spp. (earwigs) and also other arthropods ofagricultural significance such as Acari (mites) e.g. Tetranychus spp.,Panonychus spp. and Bryobia spp. (spider mites), Eriophyes spp. (gallmites), Polyphacotarsonemus spp.; Blaniulus spp. (millipedes),Scutigerella spp. (symphilids), Oniscus spp. (woodlice) and Triops spp.(crustacea); nematodes which attack plants and trees of importance toagriculture, forestry and horticulture either directly or by spreadingbacterial, viral, mycoplasma or fungal diseases of the plants, root-knotnematodes such as Meliodogyne spp. (e.g. M. incognita); cyst nematodessuch as Globodera spp. (e.g. G. rostochiensis); Heterodera spp. (e.g. H.avenae); Radopholus spp. (e.g. R. similis); lesion nematodes such asPratylenchus spp. (e.g. P. pratensis); Belonoliamus spp. (e.g. B.gracilis); Tylenchulus spp. (e.g. T. semipenetrans); Rotylenchulus spp.(e.g. R. reniformis); Rotylenchus spp. (e.g. R. robustus);Helicotylenchus spp. (e.g. H. multicinctus); Hemicycliophora spp. (e.g.H. gracilis); Criconemoides spp. (e.g. C. similis); Trichodorus spp.(e.g. T. primitivus); dagger nematodes such as Xiphinema spp. (e.g. X.diversicaudatum), Longidorus spp. (e.g. L. elongatus); Hoplolaimus spp.(e.g. H. coronatus); Aphelenchoides spp. (e.g. A. ritema-bosi, A.besseyvi); stem and bulb eelwormns such as Ditylenchus spp. (e.g. D.dipsaci).

The substances of the invention also have utility in the control ofarthropod or nematode pests of plants. The active substance is generallyapplied to the locus in which arthropod or nematode infestation is to becontrolled at a rate of about 0.005 kg to about 25 kg of active compoundper hectare of locus treated, preferably 0.02 to 2 kg/ha. Under idealconditions, depending on the pest to be controlled, the lower rate mayoffer adequate protection. On the other hand, adverse weatherconditions, resistance of the pest and other factors may require thatthe active ingredient be used in higher proportions. For foliarapplication, a rate of 0.01 to 1 kg/ha may be used.

When the pest is soil-borne, the formulation containing the activesubstance is distributed evenly over the area to be treated in anyconvenient manner. Application may be made, if desired, to the field orcrop-growing area generally or in close proximity to the seed or plantto be protected from attack. The active substance can be washed into thesoil by spraying with water over the area or can be left to the naturalaction of rainfall. During or after application, the formulation can, ifdesired, be distributed mechanically in the soil, for example byploughing or disking. Application can be prior to planting, at planting,after planting but before sprouting has taken place or after sprouting.

The substances of the invention may be applied in solid or liquidcompositions to the soil principally to control those nematodes dwellingtherein but also to the foliage principally to control those nematodesattacking the aerial parts of the plants (e.g. Aphelenchoides spp. andDitylenchus spp. listed above).

The substances of the invention are of value in controlling pests whichfeed on parts of the plant remote from the point of application, e.g.leaf feeding insects are killed by the subject substances applied toroots. In addition the substances may reduce attacks on the plant bymeans of antifeeding or repellent effects.

The substances of the invention are of particular value in theprotection of field, forage, plantation, glasshouse, orchard andvineyard crops, or ornamentals and of plantation and forest trees, forexample, cereals (such as maize, wheat, rice, sorghum), cotton, tobacco,vegetables and salads (such as beans, cole crops, curcurbits, lettuce,onions, tomatoes and peppers), field crops (such as potato, sugar beet,ground nuts, soyabean, oil seed rape), sugar cane, grassland and forage(such as maize, sorghum, lucerne), plantations (such as of tea, coffee,cocoa, banana, oil palm, coconut, rubber, spices), orchards and groves(such as of stone and pip fruit, citrus, kiwifruit, avocado, mango,olives and walnuts), vineyards, ornamental plants, flowers and shrubsunder glass and in gardens and parks, forest trees (both deciduous andevergreen) in forests, plantations and nurseries.

They are also valuable in the protection of timber (standing, felled,converted, stored or structural) from attack by sawflies (e.g. Urocerus)or beetles (e.g. scolytids, platypodids, lyctids, bostrychids,cerambycids, anobiuds), or termites, for example, Reticulitermes spp.,Heterotermes spp., Coptotermes spp.

They have applications in the protection of stored products such asgrains, fruits, nuts, spices and tobacco, whether whole, milled orcompounded into products, from moth, beetle and mite attack. Alsoprotected are stored animal products such as skins, hair, wool andfeathers in natural or converted form (e.g. as carpets or textiles) frommoth and beetle attack; also stored meat and fish from beetle, mite andfly attack.

The substances of the invention are of value in the control ofarthropods, helminths or protozoa which are injurious to, or spread oract as vectors of diseases in man and other animals, e.g. domesticanimals, such as those hereinbefore mentioned, and more especially inthe control of ticks, mites, lice, fleas, midges and biting, nuisanceand myiasis flies. The substances of the invention are also useful incontrolling arthropods, helminths or protozoa which are present, forexample, inside domestic host animals or which feed in or on the skin orsuck the blood of the animal, for which purpose they may be administeredorally, parenterally, percutaneously or topically.

According to a further aspect of the invention, there is provided aparasiticidal formulation comprising a substance of the invention, inadmixture with a compatible adjuvant, diluent or carrier. Preferably,the formulation is adapted for topical administration.

The invention further provides a substance of the invention for use as aparasiticide; and a method of treating a parasitic infestation at alocus, which comprises treatment of the locus with an effective amountof a substance of the invention. Preferably, the locus is the skin orfur of an animal, or a plant surface or the soil around the plant to betreated.

The invention further provides:

the processes described herein for preparing the compounds of formula(I) and salts and solvates thereof; pharmaceutical, veterinary oragricultural parasiticidal formulations comprising a compound of formula(I), or a pharmaceutically-, agriculturally- or veterinarily-acceptablesalt and/or solvate thereof, in admixture with a compatible adjuvant,diluent or carrier;

compounds of formula (I), and pharmaceutically- orveterinarily-acceptable salts and/or solvates, and formulations thereof,for use as a medicament;

the use of a compound of formula (I), or pharmaceutically- orveterinarily-acceptable salt therof, or formulation thereof, in themanufacture of a medicament for the treatment of a parasiticinfestation;

a method of killing or harming a parasite at a locus; and

any novel intermediates described herein.

It is to be appreciated that reference to treatment herein includesprophylaxis as well as the alleviation of established symptoms of acondition, such as a parasitic infection.

Test for Insecticidal Activity

Adult flies (Stomoxys calcitrans) are collected and anaesthetized usingCO₂- 1 μl of an acetone solution containing the test substance isapplied directly to the thorax of the fly. The flies are then placedcarefully into a 50 ml tube covered with damp gauze to recover from theCO₂. Negative controls have 1 μl of acetone dispensed onto them.Mortality is assessed 24 hours after dosing. The table below illustratesthe in vivo activity of a selection of the substances of the inventionagainst such flies. Dosages required to produce 100% mortality areexpressed in μg/fly.

Example No. Dosage 1 0.005 2 0.01 3 0.005 4 0.05 6 0.01

Test for Acaricidal Activity

A dose of 10 μg/cm² is created by evenly pipetting 0.5 ml of a 1 mg/mlsolution of the test compound in a suitable solvent such as acetone orethanol onto a Whatman No. 1 (Trade Mark) filter paper cut to a size of8×6.25 cm. When dry, the paper is folded in half, sealed on two sidesusing a crimping device and placed in a Kilner jar containing a cottonwool pad dampened with water. The jar is then sealed and placed at 25°C. for 24 hours. Next, approximately 50 Boophilus microplus larvae areintroduced into the treated paper envelope which is then crimped alongthe third side to effect a complete seal. The paper envelope is returnedto the Kilner jar, which is sealed and placed at 25° C. for a further 48hours. The papers are then removed and mortality assessed. Negativecontrols are provided by treating an appropriately cut filter paper with0.5 ml of solvent only and following the same procedure. Activity atother doses is obtained by varying the concentration of the testsolution. The table below illustrates the in vivo activity of aselection of the compounds of the invention against Boophilus micropluslarvae. Dosages are expressed in μg/cm².

Example No. Dosage/% Mortality 1 0.5  90% 2 1 100% 3 0.5 100%

The invention is illustrated by the following Examples. In the Examplesand Preparations, melting points were determined using a Gallenkampmelting point apparatus and are uncorrected. Nuclear magnetic resonance(NMR) data were obtained using a Bruker AC300 or AM300 and are quoted inparts per million using solvent or tetramethylsilane as reference. Massspectral (MS) data were obtained on a Firnigan Mat. TSQ 7000 or a FisonsInstruments Trio 1000. The calculated and observed ions quoted refer tothe isotopic composition of lowest mass. HPLC purification was performedon a 21×250mm Dynamax™ 5 μODS reverse-phase column eluted at 10ml/minute with acetonitrile: 0.005 M aqueous heptanesulphonic acid:methanol (50:40:10). Fractions were processed by evaporation of thenon-aqueous components followed by partition between ether and saturatedaqueous sodium hydrogen carbonate solution. The organic layer was thenseparated, dried and evaporated.

EXAMPLES Example 14-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole

To a solution of the title compound of Preparation 2 (210 mg) inbromoform (4ml) and dichloromethane (2ml) was added sodium hydroxide(200 mg in water (0.2 ml)) and benzyltriethylammonium chloride (10 mg),the mixture was stirred vigourously for 16 hours at room temperature.Further equivalents of sodium hydroxide (200 mg in water (0.2 ml)) andbenzyltriethylammonium chloride (10 mg) were added to the reaction,which was stirred for a further 4 days. The reaction was diluted withwater (100 ml) and extracted with dichloromethane (100 ml), the organiclayer was separated, evaporated to dryness and purified by columnchromatography on silica gel (5 g) eluted with dichloromethane:hexane(3:1) to give the title compound as a yellow crystaline solid, m.p.156-158 ° C. δ(CDCl₃): 7.76 (2H,s), 7.20 (1H,s), 2.88 (1H,dd), 2.20(1H,dd), 1.94 (1H,dd). MS (thermospray): M/Z [M+NH₄]497.9;C₁₂H₆Br₂Cl₂F₃N₃+NH₄ requires 498.0.

Example 24-(2,2-Dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole

To a solution of the title compound of Preparation 2 (200 mg) in toluene(5 ml) was added phenyl(trichloromethyl)mercury (309 mg). The mixturewas heated to 70° C. for 6 hours and then left to stir for 16 hours atroom temperature. A further mole equivalent ofphenyl(trichloromethyl)mercury (309 mg) was added, the reaction washeated to 100° C. for 8 hours and then left to stir for 16 hours at roomtemperature. The reaction was diluted with water (100 ml) and extractedwith dichloromethane (100 ml), the organic fraction was separated,evaporated to dryness and purified by column chromatography on silicagel (20 g) eluted with dichloromethane to give the title compound as apale yellow crystaline solid, m.p. 134-136° C. δ(CDCl₃): 7.78 (2H,s),7.18 (1H,s), 3.03 (1H,t), 2.20 (2H,d). MS (thermospray): M/Z [M+NH₄]407.2; C₁₂H₆Cl₄F₃N₃+NH₄ requires 407.0.

Example 33-Cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrrole

To a solution of the title compound of Preparation 5 (200mg) inbromoform (1ml), dichloromethane (0.5 ml) and ethanol (0.1 ml) was addedsodium hydroxide (100 mg in H₂O (0.1 ml)) and benzyltriethylammoniumchloride (5mg), the mixture was stirred vigourously for 3 days at roomtemperature. The reaction was diluted with water (100 ml) and extractedwith ether (100 ml), the organic fraction was separated, dried overMgSO₄, filtered, evaporated to dryness and purified by reverse phaseHPLC on C18 silica using acetonitrile:water:methanol (60:30:10) aseluent, to give the title compound as a colourless gum-like solid.δ(CDCl₃): 7.78 (2H,s), 7.18 (1H,s), 6.56 (1H,s), 2.88 (1H,dd), 2.24(1H,dd), 1.94 (1H,dd) MS (thermospray): M/Z [M+NH₄] 517.9;C₁₅H₇Br₂Cl₂F₃N₂+NH₄ requires 517.

Example 43-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)indole

To a solution of the title compound of Preparation 7 (200mg) inbromoform (4 ml) and dichloromethane (2ml) was added sodium hydroxide(200 mg in H₂O (0.2 ml)) and benzyltriethylammonium chloride (10 mg).The mixture was stirred vigourously for 16 hours at room temperature.The reaction was diluted with water (100 ml) and extracted withdichloromethane (100 ml), the organic fraction was separated, dried overMgSO₄, filtered and evaporated to dryness. The residue was purified bycolumn chromatography on silica gel (20 g) eluted withdichloromethane:hexane (1:5) to give the title compound as a colourlessgum-like solid. δ(CDCl₃): 7.72-7.90 (3H,m), 7.20-7.30 (2H,m), 6.92(1H,d), 6.84 (1H,s), 3.02 (1H, dd). 2.12 (1H,dd), 1.94 (1H,dd). M/Z[M+NH₄] 545.8; C₁₈H₁₀Br₂Cl₂F₃N+NH₄ requires 546.0.

Example 53-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-6-fluoroindole

To a solution of the title compound of Preparation 10 (20 g) inbromoform (80 ml), dichloromethane (400 ml) and ethanol (20 ml) wasadded sodium hydroxide (40 g in H₂O (40 ml)) and benzyltriethylammoniumchloride (0.80 g). The mixture was heated under reflux for 6 hours andthen stirred for a further 48 hours at room temperature. The reactionwas diluted with water (1000 ml) and extracted with dichloromethane(1000 ml), the organic fraction was separated, dried over MgSO₄,filtered and evaporated to dryness. The residue was purified by columnchromatography on silica gel (1 kg) eluted with dichloromethane to givethe title compound as a colourless gum-like solid. δ(CDCl₃): 7.70-8.00(3H,m), 6.98-7.16 (1H,m), 6.80-6.94 (1H,m 6.50-6.70 (1H,m), 2.98(1H,dd), 2.24 (1H,dd), 1.94 (1H,dd).

Example 6 3-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-triazole

To a solution of the title compound of Preparation 13 (600 mg) inbromoform (20 ml) and dichloromethane (20 ml) was added sodium hydroxide(400 mg in 0.4 ml H₂O) and benzyltriethylammonium chloride (100 mg), themixture was stirred vigourously for 3 days at room temperature. Thereaction was diluted with water (100 ml) and extracted withdichloromethane (100 ml), the organic fraction was separated, dried overMgSO₄, filtered, evaporated to dryness and purified by columnchromatography on silica gel (20 g) eluted with dichloromethane to givethe title compound as a yellow gum-like solid. δ(CDCl₃): 8.18 (1H,s),7.76 (2H,s), 3.10 (1H,dd), 2.42 (1H,dd), 2.10 (1H, dd). MS(thermospray): M/Z [M+H] 478.3; C₁₂H₆Br₂Cl₂F₃N₃+H requires 477.8.

Example 74-(3-Bromoisoxazol-5-yl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole

To a rapidly stirred solution of the compound of Preparation 14 (1.06 g)in ethyl acetate (25 ml) and water (2.5 ml) was added potassium hydrogencarbonate (0.658g) and dibromoformaldoxime (0.703 g) respectively. Thereaction was left stirring at room temperature overnight. A further0.703 g of dibromoformaldoxime was added and the reaction stirred for afurther 5 hours. The solvent was evaporated by rotary evaporation invacuo and the reaction mixture dissolved in methylene chloride (60 ml)and washed with water (2×50ml). The organics were separated, dried(MgSO₄), filtered, evaporated to dryness and purified by columnchromatography on silica gel (10 g) eluted with hexane: ethyl acetate(95:5) to give the title compound as a pale yellow solid. δ(CDCl₃): 8.20(1H,s), 7.85(2H,s), 6.97(1H,s).

Example 8 3-(3-Bromoisoxazol-5-yl)-1-(2,6-dichloro-4-trifluoromethylphenyl)indole

To a rapidly stirred solution of the title compound of Preparation 15(1.0 g) in ethyl acetate (25 ml) and water (2.5 ml) was added potassiumhydrogen carbonate (0.54 g) and dibromoformaldoxime (1.4 g)respectively. The reaction was left stirring at room temperatureovernight. The solvent was evaporated by rotary evaporation in vacuo andthe reaction mixture dissolved in methylene chloride (50 ml) and washedwith water (2×50 ml). The organics were separated, dried (Na₂SO₄),filtered, evaporated to dryness and purified by column chromatography onsilica gel (50 g) eluted with hexane followed by dichloromethane to givethe title compound as a white solid (284 mg). δ(CDCl₃): 8.0 (1H,d),7.8(2H,s), 7.7(1H,s), 7.3-7.5 (2H,m), 7.0 (1H,d), 6.6 (1H,s).

PREPARATIONS Preparation 11-(2,6-Dichloro-4-trifluoromethylphenyl)-4-iodo-1,2,3-triazole

To a solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl-1,2,3-triazole (EP-400842-A1; 1.00 g) in tetrahydrofuran (20 ml) wasadded silver trifluoroacetate (623 mg) and iodine (716 mg) at −78° C.under an atmosphere of nitrogen. The reaction was allowed to warm toroom temperature over 1 hour and then left to stir for a further 16hours. The reaction was filtered and the filtrate diluted with water(100 ml) and extracted with ether (100 ml), the organic fraction wassepararted, dried over MgSO₄, filtered and evaporated to dryness. Theresidue was purified by column chromatography (silica, 100 g) elutedwith dichloromethane:hexane (2:1) to give the title compound as a paleyellow crystalline material, m.p. 194-195° C.

Preparation 21-(2,6-Dichloro-4-trifluoromethylphenyl)-4-ethenyl-1,2,3-triazole

To a solution of the title compound of Preparation 1 (500 mg) indimethylformamide (50 ml) was added tributylvinyltin (715 μl) andtetrakis(triphenylphosphine)palladiurn (0) (50 mg). The reaction washeated to 100° C. under nitrogen for 1 hr, diluted with water (100 ml)and extracted with ether (100 ml), the organic fraction was separatedwere dried over MgSO₄, filtered and evaporated to dryness. The residuewas purified by column chromatography (silica, 50 g) eluted withdichloromethane:hexane (3:1) to give the title compound as a whitecrystaline material, m.p. 109-111° C.

Preparation 32-Amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-iodopyrrole

To a solution of2-amino-1-(2,6-dichloro4-trifluoromethylphenyl)4-cyanopyrrole (EP-372982A2) in acetonitrile (20 ml) was added N-iodosuccinimide (703 mg). Thereaction was stirred at room temperature for 30 minutes, diluted withwater (100 ml) and extracted with ether (100 ml). The organic fractionwas separated, dried over MgSO₄, filtered and evaporated to dryness, theresidue was purified by column chromatography (silica, 20 g) eluted withdichloromethane:hexane (7:3) to give the title compound as a yellowcrystaline material, m.p. 130-132° C.

Preparation 44-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-iodopyrrole

To a solution of the title compound of Preparation 3 in tetrahydrofuran(120 ml) was added tert-butyl nitrite (4 ml). The reaction was refluxedfor 1 hr and then evaporated to dryness, the residue was purified bycolumn chromatography on silica gel (500 g) eluted withdichloromethane:hexane (7:3) to give the title compound as a pale yellowcrystaline material, m.p. 118-120° C.

Preparation 53-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethenylpyrrole

To a solution of the title compound of Preparation 4 (2.50 g) indimethylformamide (100 ml) was added tributylvinyltin (5 ml) andtetrakis(triphenylphosphine) palladium (0) (300 mg). The reaction washeated to 100° C. under nitrogen for 1 hr, and the mixture wasevaporated to dryness. The residue was purified by column chromatographyon silica gel (500 g) eluted with dichloromethane:hexane (7:3) to givethe title compound as a white crystalline solid, m.p. 55-60° C.

Preparation 6 1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-formylindole

To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) indimethylformamide (10 ml) was added 3-formylindole (623 mg) andpotassium carbonate (593 mg), the mixture was heated at 90° C. for 1.5hrs. The reaction was cooled to room temperature and diluted with water(200 ml) and extracted with ether (200 ml). The organic fraction wasseparated and evaporated to dryness to give the title compound as a paleyellow crystaline material, m.p. 167-169° C.

Preparation 7 1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenylindole

To a solution of methyltriphenylphosphonium bromide (714 mg) intetrahydrofuran (20 ml) was added n-butyl lithium (0.8 ml, 2.5 M inhexanes) under nitrogen at 0° C. After 10 minutes the title compound ofPreparation 6 (700 mg) was added. The reaction was stirred for a further1 hr and then poured into an iced solution of 10% ammonium chloride (50ml), extracted with ether (100 ml), washed with brine (50 ml), driedover MgSO₄, filtered and evaporated an oil. The residue was purified bycolumn chromatography on silica gel (10 g) eluted withdichloromethane:hexane (7:3) to give the title compound as a pale yellowcrystalline material, m.p. 85-87° C.

Preparation 8 1-(2,6-Dichloro-4-trifluoromethylphenyl)-6-fluoroindole

To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (34.5 g) indimethylformamide (250 ml) was added 6-fluoroindole (34.5 g) andpotassium carbonate (20.4 g). The mixture was heated at 90° C. for 6hours and then left to stir for 16 hours at room temperature. Thereaction was diluted with water (1000 ml) and extracted with hexane(1000 ml). The organic fraction was separated and evaporated to drynessto give the title compound as a colourless liquid. δ(CDCl₃): 7.80(2H,s), 7.62 (1H,dd), 7.20 (1H,d), 6.96 (1H,dt), 6.76 (1H,d), 6.62(1H,dd.

Preparation 93-Bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-6-fluoroindole

To a solution of the title compound of Preparation 8 (37.8 g) inN,N-dimethylformamide (200 ml) was added bromine (6.8 ml) inN,N-dimethylformamide (200 ml) dropwise over 10 minutes, and thereaction was stirred at room temperature for 1 hour. The reaction wasdiluted with a solution of ammonia (10 ml) and sodium metabisulphite(2.0 g) in water (1000 ml), and extracted with hexane (2×500ml), driedover MgSO₄, filtered and evaporated to give the title compound as acolourless oil. δ(CDCl): 7.80 (2H,s), 7.60 (1H,dd), 7.22 (1H,s), 7.08(1H,dt), 6.64 (1H,dd).

Preparation 101-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenyl-6-fluoroindole

To a solution of the title compound of Preparation 9 (44.3 g) indimethylformamide (400 ml) was added tributylvinyltin (35 ml) andtetrakis(triphenylphosphine)palladium (0) (2.7 g). The reaction washeated to 70° C. for 24hrs under an atmosphere of nitrogen and then leftto stir at room temperature for a further 4 days, after whichtetrakis(triphenylphosphine)palladium(0) (2.5 g) was added and thereaction heated to 70° C. for 24hrs. The reaction mixture was evaporatedto dryness and the residue was purified by column chromatography onsilica gel (1 kg), eluted with hexane to give the title compound as acolourless oil. δ(CDCl₃): 7.74 (1H.dd), 7.80 (2H.s), 7.22 (1H,s), 7.02(1H,dt), 6.80 (1H,dd), 6.60 (1H,dd), (1H.d), 5.30 (1H, d).

Preparation 113-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-triazole:5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-triazole (60:40mixture)

To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) indimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) andpotassium carbonate (296 mg), the mixture was heated at 100° C. for2hrs. The reaction was cooled to room temperature, diluted with water(100 mL) and extracted with ether (100 ml). The organic extracts wereevaporated to dryness to give the title compounds as pale yellowcrystals.

Preparation 121-(2,6-Dichloro-4-trifluoromethylphenyl)-3-iodo-1,2,4-triazole

To a solution of the title compounds of Preparation 11 (600 mg) indiiodomethane (4 ml) was added t-butyl nitrite (2 ml), and the reactionwas stirred at room temperature for 1 hr, then diluted with water (100ml), extracted with ether (100 ml), dried over MgSO₄, filtered andevaporated to an oil. The residue was purified by column chromatography(silica, 100 g) eluted with dichloromethane:hexane (10:1) to giveexclusively the title compound as yellow crystals, m.p. 130-132° C.

Preparation 131-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenyl-1,2,4-triazole

To a solution of the title compound of Preparation 12 (204 mg) inN,N-dimethylformamide (3 ml) was added tributylvinyltin (291 μl) andtetrakis(triphenylphosphine)palladium (0) (5 mg). The reaction washeated to 90° C. under nitrogen for 5hrs, evaporated to dryness and theresidue was purified by column chromatography on silica gel (10 g)eluted with dichloromethane to give the title compound as a whitecrystals, m.p. 97-99° C.

Preparation 141-(2,6-Dichloro-4-trifluoromethylphenyl)4-ethynyl-1,2,3-triazole

To a solution of the title compound of Preparation 1 (25.02 g),trimethylsilylacetylene (260 ml) and diisopropylamine (230 ml) intetrahydrofuran, (700 ml) was added copper (I) Iodide (0.465 g) andPdCl₂(PPh₃)₂(0.865 g). The reaction mixture was heated to reflux for 5hours, evaporated to dryness and purified using column chromatography onsilica gel (350 g) eluted with dichloromethane to give a brown oil. Theresulting material was dissolved in tetrahydrofuran (500 ml), cooled to−78° C. and tetrabutylammonium fluoride (90.7 ml) was added dropwise.After the addition was complete the reaction was allowed to warm to roomtemperature, the mixture was diluted with water (250 ml), extracted withmethylene chloride (400 ml), dried (MgSO₄), filtered, evaporated todryness and purified by column chromatography on silica gel (400 g)eluted with dichloromethane : hexane (90:10). Recystallisation of thematerial in hexane yielded the title compound as a light brown solid.δ(CDCl₃): 7.93 (1H,s), 7.82 (2H,s), 3.38 (1H,s).

Preparation 15 1-(2,6-Dichloro-4-trifluoromethylphenyl)-3 -ethynylindole

To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) indimethylformamide (25 ml) was added 3-ethynylindole (2.9 g) andpotassium carbonate (2.84 g), the mixture was heated at 90° C. for 3hours under an atmosphere of nitrogen and then left to stir overnight atroom temperature. The reaction was diluted with water (100 ml) andextracted with hexane (2×100 ml). The organic fractions were separated,combined, evaporated to dryness and purified by column chromatography onsilica gel (300 g) eluted with hexane: ethylacetate (97:3) to give thetitle compound as a white solid (1.3 g), m.p. 120-122° C. δ(CDCl₃):6.9-7.8 (7H,m), 3.3 (3H,s).

What is claimed is:
 1. A method of treating a parasitic infection byadministering an effective amount of4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole.2. A method of treating a parasitic infection by administering aneffective amount of4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole.